Proteomics 2015, 15, 185–187
185
DOI 10.1002/pmic.201400592
Protein tyrosine nitration: A signaling mechanism conserved from yeast to man Serge P. Bottari Laboratory of Fundamental and Applied Bioenergetics, University Grenoble Alpes, Inserm U1055 and Centre Hospitalier Universitaire, Grenoble, France
Although protein nitration had already been reported in the late forties and found to specifically affect tyrosine residues 20 years later, it was not until the early nineties that this posttranslational modification was reported to occur in vivo in mammalian cells. Over the years, this protein modification has increasingly proven to play a major role in a variety of physiological mechanisms through redox signaling and pathological conditions through nitro-oxidative stress, from protozoan parasites to humans. In this issue (Proteomics 2015, 15, 580–590), Kang et al. report the identification of the nitroproteome during mating in the yeast Saccharomyces cerevisiae and most interestingly on the changes in nitration induced by the mating signal ␣-factor of several of these proteins. The correlation of these modifications with the biological functions of these proteins strongly suggests a role for protein nitration in mating signal transduction in yeast, thereby confirming the conservation of this pathway throughout the evolution from unicellular eukaryotes to man. The ubiquity of protein tyrosine nitration, whose importance is now also recognized in plants, further highlights its significance as an essential signaling mechanism in eukaryotes.
Received: December 12, 2014 Accepted: December 17, 2014
Keywords: Cell biology / Fluorinated carbon tags / Network analysis / Nitrotyrosine / Protein nitration / Saccharomyces cerevisiae / Yeast mating
Protein tyrosine nitration has first been reported in vitro in 1966 [1] and it was not until the pioneering work of Beckman and co-workers in the early nineties [2] that its occurrence in vivo was demonstrated, more than 30 years after protein phosphorylation [3], but only 5 years after the identification of nitric oxide (. NO) as a signaling molecule by Moncada and co-workers [4]. Interestingly and as opposed to protein phosphorylation, protein nitration is not an enzymatic but a chemical reaction generally due to the production of peroxynitrite (ONOO− ) which is the reaction product of . NO and superoxide ions (O2 .− ). Thus, . NO, which was initially viewed as a protective Correspondence: Professor Serge P. Bottari, Laboratory of Fundamental and Applied Bioenergenetics, University Grenoble Alpes, ` 2280 rue de la Piscine, 38400 St. Martin d’Heres, France E-mail: [email protected] Fax: +33-476514218
C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
factor due to its ability to scavenge O2 .− , can in fact generate a powerful oxidant. Although the rate constant at which . NO reacts with O2 .− is three times faster than the rate at which superoxide dismutase (SOD) scavenges O2 .− , the very high concentration of SOD in cells reduces the O2 .− concentration to probably less than 100 pM under “resting” conditions. NO concentrations under these same conditions are in the range of 10–100 nM, that is approximately 100-fold lower than that of SOD, meaning that very little ONOO− is formed. There are, however, a variety of physiological stimuli, for example hormones, neurotransmitters and growth factors, which increase the generation of O2 .− essentially through either the activation of NAD(P)H oxidases (NOX) or by affecting the mitochondrial respiratory chain, resulting in much higher O2 .− concentrations. This is further enhanced by subcellular compartmentalization, resulting in elevated local O2 .− concentrations that can reach or exceed . NO concentrations and thereby lead to the production of ONOO− [5] which will
www.proteomics-journal.com
186
S. P. Bottari
trigger protein nitration or S-nitrosation. The spatiotemporal organization of . NO and O2 .− generation plays a crucial role in this mechanism because of the very short lifespan of O2 .− ions. Similarly, ONOO− that also has a half-life
185
DOI 10.1002/pmic.201400592
Protein tyrosine nitration: A signaling mechanism conserved from yeast to man Serge P. Bottari Laboratory of Fundamental and Applied Bioenergetics, University Grenoble Alpes, Inserm U1055 and Centre Hospitalier Universitaire, Grenoble, France
Although protein nitration had already been reported in the late forties and found to specifically affect tyrosine residues 20 years later, it was not until the early nineties that this posttranslational modification was reported to occur in vivo in mammalian cells. Over the years, this protein modification has increasingly proven to play a major role in a variety of physiological mechanisms through redox signaling and pathological conditions through nitro-oxidative stress, from protozoan parasites to humans. In this issue (Proteomics 2015, 15, 580–590), Kang et al. report the identification of the nitroproteome during mating in the yeast Saccharomyces cerevisiae and most interestingly on the changes in nitration induced by the mating signal ␣-factor of several of these proteins. The correlation of these modifications with the biological functions of these proteins strongly suggests a role for protein nitration in mating signal transduction in yeast, thereby confirming the conservation of this pathway throughout the evolution from unicellular eukaryotes to man. The ubiquity of protein tyrosine nitration, whose importance is now also recognized in plants, further highlights its significance as an essential signaling mechanism in eukaryotes.
Received: December 12, 2014 Accepted: December 17, 2014
Keywords: Cell biology / Fluorinated carbon tags / Network analysis / Nitrotyrosine / Protein nitration / Saccharomyces cerevisiae / Yeast mating
Protein tyrosine nitration has first been reported in vitro in 1966 [1] and it was not until the pioneering work of Beckman and co-workers in the early nineties [2] that its occurrence in vivo was demonstrated, more than 30 years after protein phosphorylation [3], but only 5 years after the identification of nitric oxide (. NO) as a signaling molecule by Moncada and co-workers [4]. Interestingly and as opposed to protein phosphorylation, protein nitration is not an enzymatic but a chemical reaction generally due to the production of peroxynitrite (ONOO− ) which is the reaction product of . NO and superoxide ions (O2 .− ). Thus, . NO, which was initially viewed as a protective Correspondence: Professor Serge P. Bottari, Laboratory of Fundamental and Applied Bioenergenetics, University Grenoble Alpes, ` 2280 rue de la Piscine, 38400 St. Martin d’Heres, France E-mail: [email protected] Fax: +33-476514218
C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
factor due to its ability to scavenge O2 .− , can in fact generate a powerful oxidant. Although the rate constant at which . NO reacts with O2 .− is three times faster than the rate at which superoxide dismutase (SOD) scavenges O2 .− , the very high concentration of SOD in cells reduces the O2 .− concentration to probably less than 100 pM under “resting” conditions. NO concentrations under these same conditions are in the range of 10–100 nM, that is approximately 100-fold lower than that of SOD, meaning that very little ONOO− is formed. There are, however, a variety of physiological stimuli, for example hormones, neurotransmitters and growth factors, which increase the generation of O2 .− essentially through either the activation of NAD(P)H oxidases (NOX) or by affecting the mitochondrial respiratory chain, resulting in much higher O2 .− concentrations. This is further enhanced by subcellular compartmentalization, resulting in elevated local O2 .− concentrations that can reach or exceed . NO concentrations and thereby lead to the production of ONOO− [5] which will
www.proteomics-journal.com
186
S. P. Bottari
trigger protein nitration or S-nitrosation. The spatiotemporal organization of . NO and O2 .− generation plays a crucial role in this mechanism because of the very short lifespan of O2 .− ions. Similarly, ONOO− that also has a half-life
